Aminated fullerene-based nanoplatform enables synergistic VEGFR2-targeted anti-angiogenesis and tumor immunotherapy

Pathological angiogenesis and immunosuppression limit the efficacy of cancer therapies. Here, we report a biomimetic nanoparticle platform integrating a vascular endothelial growth factor receptor 2 (VEGFR2)-targeting aminated fullerene with tumor cell membrane coating. Phenotypic screening identified tetra [4-(amino)piperidin-1-yl]C 60 epoxide (TAPC) as a potent inhibitor of angiogenesis. Transcriptomic analyses identified VEGFR2 as a highly expressed and clinically relevant target in colorectal cancer (CRC), prompting further mechanistic investigation. TAPC was found to target VEGFR2, reducing its expression and suppressing PI3K-AKT signaling in both tumor and endothelial cells. To enhance delivery, TAPC was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles and coated with homologous tumor cell membranes to generate tumor cell membrane–coated nanoparticles (TAPC@CNPs). This formulation improved stability and supported systemic circulation, enabling tumor accumulation. In murine CRC models, TAPC@CNPs significantly inhibited tumor growth and reduced angiogenesis markers, including VEGFR2 and CD31. Furthermore, treatment decreased regulatory T-cell levels and increased T-cell infiltration and activation, indicating enhanced antitumor immunity. These findings establish TAPC as a fullerene-based VEGFR2 inhibitor and demonstrate that tumor membrane-coated nanoparticle delivery amplifies its anti-angiogenic and immune-modulating effects, offering a nanomaterial strategy to concurrently target angiogenesis and remodel the tumor immune microenvironment. • A phenotypic tube-formation screen identified TAPC as a potent aminated fullerene inhibitor of pathological angiogenesis. • TAPC directly bound to and inhibited VEGFR2, thereby blocking downstream PI3K–AKT signaling. • Tumor-cell-membrane-coated TAPC@CNPs enhanced tumor-selective delivery and anti-angiogenic efficacy. • TAPC@CNPs remodeled the tumor immune microenvironment by reducing Tregs and increasing T-cell infiltration.